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Cathepsin L is known as the most unstable lysosomal cysteine proteinase at neutral or alkaline pH. The kinetics of inactivation of human cathepsin L was studied by mixing the enzyme with a substrate and recording the release of product. The inactivation was found to be a first-order process, and the rate of the process decreased with the substrate concentration. The substrate-independent inactivation rate constant kinact was found to be 0.15 s-1 at pH 7.4 and 37 degrees C and increased 85-fold between pH 7.0 and 8.0. At pH 7.4, kinact increased 3200-fold between 5 and 37 degrees C with an energy of activation 174.7 kJ/mol. Inactive cathepsin L did not reactivate at pH 5.5. The rate of inhibition of cathepsin L by stefin B or chicken cystatin at pH 7.4 was much faster than the rate of spontaneous inactivation of the enzyme. The stefin B-cathepsin L complex incubated at pH 7.4 released active enzyme at pH 5.5, suggesting that the cysteine proteinase inhibitors might act as extracellular carriers of the cysteine proteinases.

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